Candesartan is a potent, long lasting, selective AT1 subtype angiotensin II receptor antagonist. The chemical name for candesartan is: 2-ethoxy-1-[[2′-(1H-tetrazol-5-yl) biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxyllic acid. Candesartan is angiotensin receptor blocker and blocks the ability of the chemical angiotensin II to raise the blood pressure by constricting or squeezing arteries and veins. This leads to a reduction in blood pressure. The mechanism is Angiotensin II is formed from Angiotensin I by the catalytic reaction of ACE kininase II. Angiotensin II effects stimulation of synthesis and release of aldosterone, cardiac stimulation, vasoconstriction and renal reabsorption of sodium. Candesartan blocks vasoconstrictor and aldosterone secreting effects of angiotensin II by selectively blocking the binding of angiotensin II to AT1 receptor in many tissues such as vascular smooth muscle and adrenal gland. By inhibiting the binding, candesartan disrupts the vasoconstriction mediated by AT1 receptors and thus helps patients with hypertension. In addition, by reducing the pressure against which the heart must pump blood, candesartan reduces the work of the heart and is useful in patients with heart failure.
U.S. Pat. No. 5,196,444 discloses the preparation of candesartan in 2 steps. First step is the formation of candesartan ethylester prepared by reacting cyano compound with trimethyltinazide in toluene for 4 days. The residue is separated and to it added methanol and conc. HCl. The mixture is stirred for 30 min and pH is adjusted to 3-4 with 1N NaOH. After removal of the solvent, the residue is partitioned between chloroform-water. The organic solvent is removed and the syrupy product is chromatographed. Yield is 45%
In the second step candesartan ethylester is added to 1N NaOH in ethanol and solution is stirred for 1 hr at 80° C. The reaction mass is concentrated and extracted with water and ethylacetate. The aqueous layer pH is adjusted to 3-4 with 1N HCl to give the candesartan crystals.
U.S. Pat. No. 5,703,110 describes the two step process which is a divisional of U.S. Pat. No. 5,196,444 claims candesartan, a pharmaceutically acceptable salt there of, pharmaceutical compositions and method for antagonizing angiotensin II in a mammal by administering a therapeutically effective amount of candesartan or a pharmaceutically acceptable salt thereof.
U.S. Pat. No. 6,177,587 describes the preparation of candesartan. In the first step candesartan methyl ester is prepared by reacting cyano intermediate with trioctyltinazide in toluene for 40 hours. The residue is separated and ethanol and sodium nitrite solution are added to it and the pH is adjusted to 4.5-5.5 with conc. HCl. To this solution ethyl acetate is added and the pH is adjusted to 0.5-1.5 with conc. HCl. To the solution hexane is added and again pH is adjusted to 3.5±0.5 with 4% sodium hydroxide solution. The solution is cooled to 10° C. or less and filtered to get methyl ester of candesartan.
In the second step candesartan methyl ester is added to NaOH solution and is stirred for 1-2 hr at 68-72° C. The solution is cooled and washed twice with dichloromethane and once with toluene. To the aqueous solution is added methanol and the solution pH is adjusted to 7.9±0.5 with conc. HCl. The solution is stirred at 25±5° C. for one hr which is added to water and the pH is adjusted to 3.5±0.3 with conc. HCl. The reaction mixture is diluted with water and cooled to 10° C. or less and the product candesartan formed is washed with acetone and dried.
WO 2005/051929 discloses a process where cyano intermediate is taken in toluene and to it added tributyltin chloride, sodium azide and tetrabutylammonium bromide. The resultant mass is slowly heated to 110° C. and maintained for 24 hrs at 110-115° C. After completion of the reaction, reaction mass is cooled to 15° C. and added methanol and water followed by acetic acid. Resultant mixture is stirred at 25-20° C. for 1 hr and once the product Candesartan methyl ester is separated added toluene and filtered the mass.
To this product added methanol, sodium hydroxide solution and heated to reflux for 1 hr. After completion of reaction methanol is completely removed and to the residue ethylacetate and water is added at room temperature. Stirred the mixture for 1 hr and allowed to settle at 10-15° C. The precipitate is filtered and washed twice with water to get candesartan.
The present invention is to provide one pot synthesis of candesartan without isolating the ester intermediate. Industrial advantage of the process is distillation of the reaction mass having azides to remove the candesartan ester is bypassed and the hydrolysis step is carried out insitu to get the final product candesartan.